Prime-Boost Immunization with Adenoviral · PDF filePrime-Boost Immunization with Adenoviral...
Transcript of Prime-Boost Immunization with Adenoviral · PDF filePrime-Boost Immunization with Adenoviral...
Prime-Boost Immunization with Adenoviral Vaccines
Robert A. Seder, M.D. April 18th, 2012
Dale and Betty Bumpers
Vaccine Research Center National Institute of Allergy and Infectious Diseases National Institutes of Health
Immune Requirements for Vaccines: HIV, Malaria and Tuberculosis
• HIV, Malaria and TB vaccination will require generation of antibody and/or T cell responses: • Phase III efficacy trials for HIV and Malaria have shown ~30%
protection correlating with antibody • CD8+ T cells will improve HIV viral control or malaria in the liver
• CD8+ T cells can be induced by:
• Protein/DC Targeted Vaccines: • Requires cross-presentation-low magnitude
• DNA Vaccines: Require multiple immunizations • Viral Vaccine Vectors:
• Most efficient method of inducing robust T cell immunity
Priming: How do novel chAds compare to human rAds for
induction of protective CD8 T cell responses?
Question
Experimental Outline
Day 0 Vaccinate
Group: Vaccine:
1 rAd5:SIV-Gag
2 rAd28:SIV-Gag
3 rAd35:SIV-Gag
6 chAd3:SIV-Gag
7 chAd63:SIV-Gag
8 PBS
Days 14, 21, 28, 35 and 70 Peripheral blood- CD8+ SIV Gag Tetramer time course
• Administered each vector : •1 x 109 PU
•1 x 108 PU
•1 x 107 PU
• Vaccinated SQ in footpad
Day 90-100 Infectious challenge
Dose Titration of Vectors Correlates With Hierarchy Observed in Clinical Studies
SIV-Gag specific CD8+
T cells (%)
Days after vaccination
rAd5 rAd28 rAd35
chAd63 chAd3
1 x 109 PU 1 x 108 PU 1 x 107 PU PBS
Key to dose:
0 25 50 750
5
10
15
20
25
30
0 25 50 750
5
10
15
20
25
30
A Predictive Hierarchy for CD8+ T Cell Immunity Is Observed at 1 x 107 PU Dose
SIV-Gag specific CD8+ T cells (%)
0 25 50 750
5
10
15
20
25
30
rAd5 rAd28 rAd35 PBS
Key to vectors: rAd5 chAd3 chAd63 PBS
Key to vectors:
0 25 50 750
5
10
15
20
25
30
0 25 50 750
5
10
15
20
25
30
0 25 50 750
5
10
15
20
25
30
SIV Gag specific CD4+ T cell responses were low and comparable for all Ads
TNF+ IL-2+ TNF+ IL-2+
IFN-g+ TNF+ IL-2+
IFN-g+
Differentiation Terminal effector
Naïve cell
IFN-g+ TNF+
IFN-g+ IL-2+
CD8
IFN-g
TNF
CD4
T Cell Quality
Darrah et al, Nat Med, 2007: Using Leishmania major infection model: • Protective vaccines induced CD4 Th1 cells
that co-expressed IFN-g, IL-2 and TNF • CD4 Th1 cells that co-expressed 3
cytokines had higher MFI
3 cytokines 2 cytokines 1 cytokine Key to IFN-g, IL-2 and TNF co-expression:
Betts et al, Blood, 2006: Using HIV long-term non-progressors: • Lower long-term viral load has more multi-
functional cells • Includes MIP1b, CD107a (degranulation)
In spleen at day 70 post-vaccination:
G+ 2+ T+ G+ 2+ T- G+ 2- T+ G+ 2- T- G- 2+ T+ G- 2+ T- G- 2- T+ Key:
rAd5:
1 x 109 PU 1 x 108 PU 1 x 107 PU
Quality of Ad5 CD8+ T Cells
CFUs in spleen (log10)
1 x 10e9 PU 1 x 10e8 PU Key: 1 x 10e7 PU
rAd5 rAd28 rAd35 PBS chAd63 chAd3 PBS rAd5
Protection Against Listeria-SIV Correlates With CD8 Response Magnitude
0 5 10 153
4
5
6
7
hAd5 Control
aCD4 aCD8
+ - - - - - - -
+ + - -
+ - + -
+ - - +
+ - + +
% SIV Gag CD8 T cells
CFUs in spleen (log10)
0 5 10 153
4
5
6
7 y = -0.1647x + 5.4151 R² = 0.27259 P < 0.0001
• Chimp-derived Ad vectors potently induce Gag- specific CD8+ T cell responses • Have a broad range of effective dose compared to low
sero-prevalent human-derived vectors • chAd3 protects against Listeria challenge at all doses
and against Ebola in NHP
•Dose titration highlights hierarchy in magnitude and protective capacity responses between the vectors at the lowest dose:
Summary
rAd5 rAd35 ≈ chAd3 > chAd63 = rAd28 > >>
• What is the mechanistic basis for the hierarchy in CD8 immunity? • How do these vectors differ in:
• Amount or duration of antigen expression? • Innate immunity?
Question
Prime-Boost Immunization for HIV Vaccines
• HIV Phase III Trials
– ALVAC (Env/Gag)-Env Protein/Alum (RV-144)-~30% Protection
– DNA (Env/Gag)-Ad5 (Env/Gag) (HVTN 505)-Ongoing
Ongoing and Future Clinical Studies
– DNA-Pox (MVA, NYVAC)
– Ad26-MVA
Question: What is optimal Prime-Boost Regimen for inducing robust HIV Env and Gag immunity
Prime-Boost Immunization for HIV Vaccines
• Prime
– Compare DNA vs rAd priming- Does the magnitude of the primed CD8+ T cell response correlate with improved immunity after boosting?
• Boost
– Compare potency of Pox versus Ad viral boost for CD4 and CD8+ T cell responses
0 10 20 30 40 50 60 700
10
20
30
40
50
rAd28 / -
- / rAd5
- / chAd3
- / -0 10 20 30 40 50 60 70
0
10
20
30
40
50
rAd28 / rAd5
rAd28 / chAd3
rAd28 / -
- / rAd5
- / chAd3
- / -0 10 20 30 40 50 60 70
0
10
20
30
40
50
rAd28 / -
- / -0 10 20 30 40 50 60 70
0
10
20
30
40
50
0 10 20 30 40 50 60 700
5
10
15
20
25
30
35
0 10 20 30 40 50 60 700
5
10
15
20
25
30
35
DNA / -
- / rAd5
- / chAd3
- / -0 10 20 30 40 50 60 70
0
5
10
15
20
25
30
35
DNA / rAd5
DNA / chAd3
DNA / -
- / rAd5
- / chAd3
- / -
rAd5 and chAd3 Strongly Boost DNA or Ad28 Primed CD8+ T Cell Responses
0 10 20 30 40 50 60 700
5
10
15
20
25
30
35
DNA / -
- / -
Key to Prime / Boost:
Key to Prime / Boost:
Days after boost
% of CD3+CD8+ T cells that are
Tetramer+
NYVAC Boosts Ad-Primed CD8 T cell Responses More Robustly than Heterologous chAd3
Days after boost
Key to Prime / Boost:
Key to Prime / Boost:
% of CD3+CD8+ T cells that are
Tetramer+
0 10 20 30 40 50 60 700
5
10
15
20
25
30
35
chAd3 boosted
0 10 20 30 40 50 60 700
10
20
30
40
50
60
70
NYVAC boosted
0 10 20 30 40 50 60 700
5
10
15
20
25
30
35
PBS
0 10 20 30 40 50 60 700
5
10
15
20
25
30
35
chAd3
PBS
0 10 20 30 40 50 60 700
5
10
15
20
25
30
35
rAd5
rAd28
rAd35
chAd3
PBS
0 10 20 30 40 50 60 700
10
20
30
40
50
60
70
rAd5
rAd28
rAd35
chAd3
PBS
0 10 20 30 40 50 60 700
10
20
30
40
50
60
70
rAd5
rAd28
rAd35
chAd3
PBS
0 10 20 30 40 50 60 700
10
20
30
40
50
60
70
rAd35
PBS
0 10 20 30 40 50 60 700
10
20
30
40
50
60
70
PBS
Prime-Boost Immunization with Ad and Pox Induce Potent HIV Env Specific CD4+ T Cell Responses
rAd 5
rAd 28
rAd 35
chAd 3
MVA chAd 3 Ctl
MVA Boost
chAd 63
rAd 5
rAd 28
rAd 35
chAd 3
MVA chAd 3 Ctl
Priming
chAd 63
HIV Env CD4+/IFN-g
Responses (%)
Time of Boost Peak Post Boost
Quality of a Primed-Boosted CD4+ T Cell Response
rAd5 rAd28 rAd35 MVA
Time of MVA boost
Peak post MVA boost
rAd5 rAd28 rAd35 MVA
Ad prime at 1 x 108 PU:
G+ 2+ T+ G+ 2+ T- G+ 2- T+ G+ 2- T- G- 2+ T+ G- 2+ T- G- 2- T+
Key to pies:
Key to arc: IFNγ production
Prime-Boost Immunization with Ad and Pox Induce Potent HIV Env Specific CD8+ T Cell Responses
rAd 5
rAd 28
rAd 35
chAd 3
MVA chAd 3 Ctl
MVA Boost
chAd 63
rAd 5
rAd 28
rAd 35
chAd 3
MVA chAd 3 Ctl
Priming
chAd 63
HIV Env CD8+/IFN-g
Responses (%)
Time of Boost Peak Post Boost
Quality of a Primed-Boosted CD8+ T Cell Response
rAd5 rAd28 rAd35 MVA
Time of MVA boost
Peak post MVA boost
rAd5 rAd28 rAd35 MVA
Ad prime at 1 x 108 PU:
G+ 2+ T+ G+ 2+ T- G+ 2- T+ G+ 2- T- G- 2+ T+ G- 2+ T- G- 2- T+
Key to pies:
Key to arc: IFNγ production
• Priming:
•Ad 28, ChAd 3, ChAd 63 efficiently prime T cells •Ad35 is limited for priming CD4 and CD8 T cell immunity •Pox viral vectors are limited for priming CD8+ T cells
• Boosting:
• Pox viral vectors potently boost CD4, CD8 and Ab responses and are true heterologous boost following Ad priming • Multiple Ad vectors boost T cell responses
•Maintenance:
•For CD4+ T cells and antibody- pox or protein/adjuvant vaccines can be used •For CD8+ T cells will need Ad or Pox
Summary: Lessons Learned